PM01183 (lurbinectedin) is an investigational anticancer drug that blocks transactivated transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment. Its activity has been observed in several different tumor types, and in patients who are resistant to platinum-based chemotherapy. Due to PM01183’s observed activity in homologous recombination-deficient cell lines, this phase 2 trial was initiated in patients with metastatic breast cancer and germline BRCA mutations (BRCAmut). In highlighting an unmet need in this population of patients, Dr Judith Balmaña of Barcelona, Spain, who was affiliated with this study, said, “There are no approved therapies specifically for breast cancer patients with a BRCA1/2 mutation, and these patients are being treated mainly according to their hormone receptor and HER2 [human epidermal growth factor receptor 2] status.”
BRCAmut patients with metastatic breast cancer who had had fewer than 3 chemotherapy regimens in the advanced/metastatic setting were eligible for inclusion in this study. Additionally, included patients had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines, minimal disease-related symptoms (performance status ≤1), and adequate major organ function. Patients received PM01183 intravenously once every 3 weeks. Planned dosing was adjusted during the course of the trial from an initial fixed dose of 7 mg to 3.5 mg/m2 to improve safety. The primary end point of this trial was overall response rate (ORR) by RECIST v1.1.
As of May 2016, 54 eligible patients (median age, 43 years; median, 1 prior advanced chemotherapy treatment) had been treated. A total of 35 patients had received the 7-mg fixed dose; 19 patients had received the 3.5-mg/m2 dosing). Of the 51 evaluable patients, ORR was 39% (95% confidence interval [CI], 26-54), with 43% of patients having stable disease, 37% having partial response, 18% having progressive disease, and 2% having complete response. The median duration of response was 4.6 months (95% CI, 3.4-11.3), and the median progression-free survival was ≥4.1 months (95% CI, 2.6-6.0). Of the 22 responding patients, 5 had ongoing response at the time of data cut-off for this report. For patients having received prior treatments with platinum-based chemotherapies, ORR was 23% (95% CI, 9-44).
The most common grade 3-4 related adverse events by dose (7-mg fixed dose/3.5 mg/m2) were neutropenia 71%/50% (grade 4: 51%/6%); febrile neutropenia 29%/6%; thrombocytopenia 26%/6% (grade 4: 20%/0%); grade 3 fatigue 17%/17%; transaminase increase 26%/11% (grade 4: 3%/0%); and grade 3 nausea 9%/6%.
These results confirm that PM01183 is an active drug in BRCAmut patients with metastatic breast cancer, including in those who have received prior platinum-based treatments. Efficacy was maintained at the adjusted 3.5-mg/m2 dosage, while tolerance was notably improved. Further development of this therapy is currently underway with the planning of a phase 3 trial.
Balmaña J, et al. ESMO 2016. Abstract 223O.